A consensus is building that several epilepsy disorders, including Temporal lobe epilepsy (TLE), a partial adult onset form of human epilepsy, are often associated with significant long-term cognitive impairments. Currently, no effective treatment options exist to prevent or reverse epilepsy-related memory loss, and the underlying molecular mechanisms remain elusive. Recent work from our lab and others has implicated abnormal epigenetic DNA methylation (DNAme) regulation in epilepsy. Thus, we propose that DNAme may be a major contributor of aberrant gene transcription in the epileptic hippocampus. Because, previous studies have demonstrated that brain derived neurotrophic factor (Bdnf) gene expression is required for memory formation and is significantly dysregulated in the hippocampi of both epileptic patients and spontaneously seizing rats, we will focus our studies by investigating epigenetic regulation of Bdnf at excitatory synapses in the hippocampus during memory formation with TLE. Intriguingly, the role of epigenetics in mediating behaviorally- induced Bdnf gene expression changes in the epileptic hippocampus is largely uncharacterized. We will manipulate DNAme with DNMT inhibitors and Methionine in our experimental model of TLE, to gain insights into potential therapeutic targets for the treatment of epilepsy-related memory loss. Since these inhibitors are already in use clinically or being aggressively studied and developed in oncology, there is the potential to rapidly translate to treatments for epilepsy-related memory impairments and other comorbidities such as depression and anxiety in humans. The central hypothesis of this proposal is that aberrant DNAme mediated transcriptional regulation of memory permissive genes, like Bdnf, in the epileptic hippocampus contributes to epilepsy-related memory impairments. Using novel methodical and technical approaches, the aims of this proposal are as follows: 1) to test whether Bdnf gene regulation by DNAme is altered in CA1 pyramidal neurons during memory formation in an experimental rodent model of TLE, and 2) to test whether treatment with methionine reverses two-epileptic phenotypes, hippocampal network hyperactivity and hippocampus-dependent memory formation in TLE. Understanding the pathophysiological mechanisms of memory deficits associated with TLE at the cellular and molecular levels and evaluation of potential therapeutic strategies undoubtedly take priority in the path of research on cognitive impairments associated with this neurological disorder.